Essential role for orbitofrontal serotonin 1B receptors in obsessive-compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice.
Essential role for orbitofrontal serotonin 1B receptors in obsessive-compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice.
复制标题
轨道额5-羟色胺1B受体在强迫症样行为和5-羟色胺再摄取抑制剂反应中的重要作用。
DOI：
10.1016/j.biopsych.2011.07.032
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发表时间：
2011-12-01
影响因子：
10.6
通讯作者：
Dulawa, Stephanie C.
中科院分区：
文献类型：
--
作者：
Shanahan, Nancy A.;Velez, Lady P.;Masten, Virginia L.;Dulawa, Stephanie C.
关键词：
持续性和感觉运动门控缺陷是强迫症（OCD）的核心特征。5-羟色胺1B受体（5-HT 1BR）激动剂可加重患者的强迫症症状，并诱导小鼠出现持续性和感觉运动门控缺陷。5-羟色胺再摄取抑制剂（SRI），而不是去甲肾上腺素再摄取抑制剂（NRI），在治疗4-8周后减轻强迫症症状。使用小鼠，我们比较了慢性SRI与NRI治疗对5-HT 1BR诱导的强迫症样行为的影响，以及眶额皮质下“强迫症回路”中5-HT 1BR的敏感性。此外，我们定位了介导强迫症样行为的5-HT 1BR群体。小鼠长期接受SRI氯丙咪嗪或NRI地昔帕明，并检查5-HT 1BR诱导的强迫症样行为，或5-HT 1BR结合和G蛋白偶联在尾壳核，丘脑核和眶额皮质。在SRI治疗4、14、21、28或56天后，测试单独小鼠的强迫症或抑郁样行为。最后，在眶额内5-HT 1BR激动剂输注或眶额内5-HT 1BR拮抗剂输注联合全身5-HT 1BR激动剂治疗后评估OCD样行为。有效的，但不是无效的，强迫症治疗减少了强迫症样行为的时间过程中，平行于延迟的治疗开始在强迫症患者，并下调5-HT 1BR表达的眶额皮质。眶额内5-HT 1BR激动剂输注诱导了OCD样行为，而眶额内5-HT 1BR拮抗剂输注阻断了全身5-HT 1BR激动剂治疗的OCD样作用。这些结果表明，眶额5-HT 1BRs是必要的，足以诱导小鼠的强迫症样行为，SRI药物治疗通过脱敏眶额5-HT 1BRs减少强迫症样行为。我们的研究结果表明，眶额5-HT 1BRs在强迫症的病理生理和治疗中起着重要作用。
Perseveration and sensorimotor gating deficits are core features of obsessive-compulsive disorder (OCD). Serotonin 1B receptor (5-HT1BR) agonists exacerbate OCD symptoms in patients, and induce perseveration and sensorimotor gating deficits in mice. Serotonin reuptake inhibitors (SRIs), but not noradrenaline reuptake inhibitors (NRIs), reduce OCD symptoms following 4–8 weeks of treatment. Using mice, we compared the effects of chronic SRI versus NRI treatment on 5-HT1BR-induced OCD-like behavior, and 5-HT1BR sensitivity in orbitofrontal-subcortical “OCD circuits”. Furthermore, we localized the 5-HT1BR population that mediates OCD-like behavior. Mice chronically received the SRI clomipramine or the NRI desipramine and were examined for 5-HT1BR-induced OCD-like behavior, or 5-HT1BR binding and G-protein-coupling in caudate-putamen, nucleus accumbens, and orbitofrontal cortex. Separate mice were tested for OCD- or depression-like behavior following 4, 14, 21, 28 or 56 days of SRI treatment. Finally, OCD-like behavior was assessed following intra-orbitofrontal 5-HT1BR agonist infusion, or intra-orbitofrontal 5-HT1BR antagonist infusion coupled with systemic 5-HT1BR agonist treatment. Effective, but not ineffective, OCD treatments reduced OCD-like behavior in mice with a time-course that parallels the delayed therapeutic onset in OCD patients, and downregulated 5-HT1BR expression in the orbitofrontal cortex. Intra-orbitofrontal 5-HT1BR agonist infusion induced OCD-like behavior, and intra-orbitofrontal 5-HT1BR antagonist infusion blocked OCD-like effects of systemic 5-HT1BR agonist treatment. These results indicate that orbitofrontal 5-HT1BRs are necessary and sufficient to induce OCD-like behavior in mice, and that SRI pharmacotherapy reduces OCD-like behavior by desensitizing orbitofrontal 5-HT1BRs. Our findings suggest an essential role for orbitofrontal 5-HT1BRs in OCD pathophysiology and treatment.
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